The serotype distribution among healthy carriers before vaccination is essential for predicting the impact of pneumococcal conjugate vaccine on invasive disease.

Pneumococcal conjugate vaccines (PCVs) have substantially reduced morbidity and mortality of pneumococcal disease. The impact of the 7-valent PCV on all-serotype invasive pneumococcal disease (IPD) among children was reported to vary between high-income countries. We investigate the ability to predict this heterogeneity from pre-vaccination data. We propose a parsimonious model that predicts the impact of PCVs from the odds of vaccine serotype (VT) among carriers and IPD cases in the pre-PCV period, assuming that VT are eliminated in a mature PCV programme, that full serotype replacement occurs in carriage and that invasiveness of the NVT group is unchanged. We test model performance against the reported impact of PCV7 on childhood IPD in high-income countries from a recent meta-analysis. The odds of pre-PCV7 VT IPD, PCV schedule, PCV coverage and whether a catch up campaign was used for introduction was gathered from the same analysis. We conducted a literature review and meta-analysis to obtain the odds of pre-PCV7 VT carriage in the respective settings. The model predicted the reported impact on childhood IPD of mature PCV programmes; the ratio of predicted and observed incidence risk ratios was close to 1 in all settings. In the high income settings studied differences in schedule, coverage, and catch up campaigns were not associated with the observed heterogeneity in impact of PCV7 on childhood all-serotype IPD. The pre-PCV7 proportion of VT IPD alone also had limited predictive value. The pre-PCV7 proportion of VT carriage and IPD are the main determinants for the impact of PCV7 on childhood IPD and can be combined in a simple model to provide predictions of the vaccine preventable burden of IPD

The Enduring Challenge of Determining Pneumonia Etiology in Children: Considerations for Future Research Priorities.

Pneumonia kills more children each year worldwide than any other disease. Nonetheless, accurately determining the causes of childhood pneumonia has remained elusive. Over the past century, the focus of pneumonia etiology research has shifted from studies of lung aspirates and postmortem specimens intent on identifying pneumococcal disease to studies of multiple specimen types distant from the lung that are tested for multiple pathogens. Some major challenges facing modern pneumonia etiology studies include the use of nonspecific and variable case definitions, poor access to pathologic lung tissue and to specimens from fatal cases, poor diagnostic accuracy of assays (especially when testing nonpulmonary specimens), and the interpretation of results when multiple pathogens are detected in a given individual. The future of childhood pneumonia etiology research will likely require integrating data from complementary approaches, including applications of advanced molecular diagnostics and vaccine probe studies, as well as a renewed emphasis on lung aspirates from radiologically confirmed pneumonia and postmortem examinations

The burden of acute respiratory infections in crisis-affected populations: a systematic review

Crises due to armed conflict, forced displacement and natural disasters result in excess morbidity and mortality due to infectious diseases. Historically, acute respiratory infections (ARIs) have received relatively little attention in the humanitarian sector. We performed a systematic review to generate evidence on the burden of ARI in crises, and inform prioritisation of relief interventions. We identified 36 studies published since 1980 reporting data on the burden (incidence, prevalence, proportional morbidity or mortality, case-fatality, attributable mortality rate) of ARI, as defined by the International Classification of Diseases, version 10 and as diagnosed by a clinician, in populations who at the time of the study were affected by natural disasters, armed conflict, forced displacement, and nutritional emergencies. We described studies and stratified data by age group, but did not do pooled analyses due to heterogeneity in case definitions. The published evidence, mainly from refugee camps and surveillance or patient record review studies, suggests very high excess morbidity and mortality (20-35% proportional mortality) and case-fatality (up to 30-35%) due to ARI. However, ARI disease burden comparisons with non-crisis settings are difficult because of non-comparability of data. Better epidemiological studies with clearer case definitions are needed to provide the evidence base for priority setting and programme impact assessments. Humanitarian agencies should include ARI prevention and control among infants, children and adults as priority activities in crises. Improved data collection, case management and vaccine strategies will help to reduce disease burden

Particle tracking in a salinity gradient: A method for measuring sinking rate of individual phytoplankton in the laboratory

This paper presents a new method to measure the sinking rates of individual phytoplankton “particles” (cells, chains, colonies, and aggregates) in the laboratory. Conventional particle tracking and high resolution video imaging were used to measure particle sinking rates and particle size. The stabilizing force of a very mild linear salinity gradient (1 ppt over 15 cm) prevented the formation of convection currents in the laboratory settling chamber. Whereas bulk settling methods such as SETCOL provide a single value of sinking rate for a population, this method allows the measurement of sinking rate and particle size for a large number of individual particles or phytoplankton within a population. The method has applications where sinking rates vary within a population, or where sinking rate-size relationships are important. Preliminary data from experiments with both laboratory and field samples of marine phytoplankton are presented here to illustrate the use of the technique, its applications, and limitations. Whereas this paper deals only with sinking phytoplankton, the method is equally valid for positively buoyant species, as well as nonbiological particles

Estimating the burden of pneumococcal pneumonia among adults: a systematic review and meta-analysis of diagnostic techniques

Background: Pneumococcal pneumonia causes significant morbidity and mortality among adults. Given limitations of diagnostic tests for non-bacteremic pneumococcal pneumonia, most studies report the incidence of bacteremic or invasive pneumococcal disease (IPD), and thus, grossly underestimate the pneumococcal pneumonia burden. We aimed to develop a conceptual and quantitative strategy to estimate the non-bacteremic disease burden among adults with community-acquired pneumonia (CAP) using systematic study methods and the availability of a urine antigen assay. Methods and Findings: We performed a systematic literature review of studies providing information on the relative yield of various diagnostic assays (BinaxNOW® S. pneumoniae urine antigen test (UAT) with blood and/or sputum culture) in diagnosing pneumococcal pneumonia. We estimated the proportion of pneumococcal pneumonia that is bacteremic, the proportion of CAP attributable to pneumococcus, and the additional contribution of the Binax UAT beyond conventional diagnostic techniques, using random effects meta-analytic methods and bootstrapping. We included 35 studies in the analysis, predominantly from developed countries. The estimated proportion of pneumococcal pneumonia that is bacteremic was 24.8% (95% CI: 21.3%, 28.9%). The estimated proportion of CAP attributable to pneumococcus was 27.3% (95% CI: 23.9%, 31.1%). The Binax UAT diagnosed an additional 11.4% (95% CI: 9.6, 13.6%) of CAP beyond conventional techniques. We were limited by the fact that not all patients underwent all diagnostic tests and by the sensitivity and specificity of the diagnostic tests themselves. We address these resulting biases and provide a range of plausible values in order to estimate the burden of pneumococcal pneumonia among adults. Conclusions: Estimating the adult burden of pneumococcal disease from bacteremic pneumococcal pneumonia data alone significantly underestimates the true burden of disease in adults. For every case of bacteremic pneumococcal pneumonia, we estimate that there are at least 3 additional cases of non-bacteremic pneumococcal pneumonia

Immunization: vital progress, unfinished agenda.

Vaccination against infectious diseases has changed the future of the human species, saving millions of lives every year, both children and adults, and providing major benefits to society as a whole. Here we show, however, that national and sub-national coverage of vaccination varies greatly and major unmet needs persist. Although scientific progress opens exciting perspectives in terms of new vaccines, the pathway from discovery to sustainable implementation can be long and difficult, from the financing, development and licensing to programme implementation and public acceptance. Immunization is one of the best investments in health and should remain a priority for research, industry, public health and society

Addressing the Analytic Challenges of Cross-Sectional Pediatric Pneumonia Etiology Data.

Despite tremendous advances in diagnostic laboratory technology, identifying the pathogen(s) causing pneumonia remains challenging because the infected lung tissue cannot usually be sampled for testing. Consequently, to obtain information about pneumonia etiology, clinicians and researchers test specimens distant to the site of infection. These tests may lack sensitivity (eg, blood culture, which is only positive in a small proportion of children with pneumonia) and/or specificity (eg, detection of pathogens in upper respiratory tract specimens, which may indicate asymptomatic carriage or a less severe syndrome, such as upper respiratory infection). While highly sensitive nucleic acid detection methods and testing of multiple specimens improve sensitivity, multiple pathogens are often detected and this adds complexity to the interpretation as the etiologic significance of results may be unclear (ie, the pneumonia may be caused by none, one, some, or all of the pathogens detected). Some of these challenges can be addressed by adjusting positivity rates to account for poor sensitivity or incorporating test results from controls without pneumonia to account for poor specificity. However, no classical analytic methods can account for measurement error (ie, sensitivity and specificity) for multiple specimen types and integrate the results of measurements for multiple pathogens to produce an accurate understanding of etiology. We describe the major analytic challenges in determining pneumonia etiology and review how the common analytical approaches (eg, descriptive, case-control, attributable fraction, latent class analysis) address some but not all challenges. We demonstrate how these limitations necessitate a new, integrated analytical approach to pneumonia etiology data

Epidemiology and etiology of childhood pneumonia in 2010:estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries

BACKGROUND: The recent series of reviews conducted within the Global Action Plan for Pneumonia and Diarrhoea (GAPPD) addressed epidemiology of the two deadly diseases at the global and regional level; it also estimated the effectiveness of interventions, barriers to achieving high coverage and the main implications for health policy. The aim of this paper is to provide the estimates of childhood pneumonia at the country level. This should allow national policy–makers and stakeholders to implement proposed policies in the World Health Organization (WHO) and UNICEF member countries. METHODS: We conducted a series of systematic reviews to update previous estimates of the global, regional and national burden of childhood pneumonia incidence, severe morbidity, mortality, risk factors and specific contributions of the most common pathogens: Streptococcus pneumoniae (SP), Haemophilus influenzae type B (Hib), respiratory syncytial virus (RSV) and influenza virus (flu). We distributed the global and regional–level estimates of the number of cases, severe cases and deaths from childhood pneumonia in 2010–2011 by specific countries using an epidemiological model. The model was based on the prevalence of the five main risk factors for childhood pneumonia within countries (malnutrition, low birth weight, non–exclusive breastfeeding in the first four months, solid fuel use and crowding) and risk effect sizes estimated using meta–analysis. FINDINGS: The incidence of community–acquired childhood pneumonia in low– and middle–income countries (LMIC) in the year 2010, using World Health Organization's definition, was about 0.22 (interquartile range (IQR) 0.11–0.51) episodes per child–year (e/cy), with 11.5% (IQR 8.0–33.0%) of cases progressing to severe episodes. This is a reduction of nearly 25% over the past decade, which is consistent with observed reductions in the prevalence of risk factors for pneumonia throughout LMIC. At the level of pneumonia incidence, RSV is the most common pathogen, present in about 29% of all episodes, followed by influenza (17%). The contribution of different pathogens varies by pneumonia severity strata, with viral etiologies becoming relatively less important and most deaths in 2010 caused by the main bacterial agents – SP (33%) and Hib (16%), accounting for vaccine use against these two pathogens. CONCLUSIONS: In comparison to 2000, the primary epidemiological evidence contributing to the models of childhood pneumonia burden has improved only slightly; all estimates have wide uncertainty bounds. Still, there is evidence of a decreasing trend for all measures of the burden over the period 2000–2010. The estimates of pneumonia incidence, severe morbidity, mortality and etiology, although each derived from different and independent data, are internally consistent – lending credibility to the new set of estimates. Pneumonia continues to be the leading cause of both morbidity and mortality for young children beyond the neonatal period and requires ongoing strategies and progress to reduce the burden further

The Potential for Reducing the Number of Pneumococcal Conjugate Vaccine Doses While Sustaining Herd Immunity in High-Income Countries.

Stefan Flasche and colleagues consider whether the number of PCV doses in the infant schedule could be reduced without compromising its public health benefit in high-income settings